Can the metabolic characteristics of diffuse glioma on <sup>11</sup>C-methionine PET/CT serve as a marker of its IDH status? Cross sectional study

Abstract

INTRODUCTION: Since 2016, molecular markers, in particular, mutations in isocitrate dehydrogenase (IDH) 1 and 2, have been introduced as a classifying feature of cerebral gliomas that provided superior prognostication. The search for non-invasive biomarkers of the molecular profile of gliomas is necessary to improve the quality of preoperative diagnostics, identify patients with good and poor prognosis and determine treatment tactics.OBJECTIVE: Was to study the relationship between the IDH genotype of diffuse cerebral gliomas and metabolic biomarkers according to the results of PET/CT with [11C]methionine.MATERIALS AND METHOD: The results of PET/CT with 11C-methionine were identified to a retrospective analysis of 260 patients aged 18 to 75 years (median 40 years) with untreated cerebral glioma. Based on histological and molecular genetic studies of the surgical material including the determination of a mutation in the isocitrate dehydrogenase 1 (IDH1132H) gene, diffuse gliomas were classified according to the 2016 WHO classification of CNS tumors. Metabolic biomarkers included the calculation of tumor-to-brain ratio of 11С-methionine (TBRmax, TBRpeak and TBRmean) as well as the metabolic tumor volume (MTV). Statistics. Non-parametric tests were performed to compare the differences among patient groups. ROC curve analysis was performed to screen the optimal parameter and its best cutoff value for the discrimination of glioma genotype. All data analyses were performed using “Statistica 10,0” and “MedCalc” ststistical software. p-values less than 0.05 were considered statistically significant.RESULTS: According to the 2016 WHO classification astrocytic and oligodendroglial tumors of the adult type were divided into three groups: astrocytic gliomas with a mutation in the IDH1 gene (IDH1 mut) (n=95), astrocytic gliomas without a mutation in the IDH1 gene (IDH1 wild type — IDH1 wt) (n=103), and IDH1-mutant oligodendrogliomas (n=62). Significant differences in all ratios between the three molecular groups of gliomas were established. TBRmax cutoff of 2.27 differentiated between IDH1 wt and IDH1 mut gliomas with a sensitivity of 61% and a specificity of 77% (area under curve — AUC 0.752). When considering subgroups of gliomas that are homogeneous in terms of the IDH1 status or Grade, the dependence of TBR on the glioma histotype and grading was additionally established. In IDH1 mut oligodendrogliomas, TBR was significantly higher than in mutant astrocytomas, and in IDH1 wt astrocytomas, significant differences in TBR were established between Grade 2 and Grade 3–4. TBRmax was not a predictor of glioma type according to the WHO 2016 classification due to significant overlap of individual of TBR values. But TBRmax allowed diagnosing a cluster of malignant gliomas, including glioblastoma and astrocytoma Grade 3 IDH wt, as well as oligodendroglioma Grade 3 IDH1 mut, with a sensitivity of 65% and a specificity of 89% (AUC 0.848) at a cutoff of TBR=2.7. A strong correlation between the three tumor-to-brain ratios allows any ratio to be used in diagnostics. There were no significant differences in MTV between molecular types of gliomas.DISCUSSION: Distinguishing glioma types based on the 2016 WHO classification of the CNS tumors on the basis of 11Cmethionine uptake seems to be not reliable due to many factors that affect its uptake. In astrocytomas high TBR is associated with malignant grade and wild type IDH1 gene. However, the lack of differences in TBR between these astrocytomas and Grade 3 IDH1-mutant oligodendrogliomas does not allow one to predict the IDH1 status of the tumor in the absence of other radiological signs of the glioma histotype. The absence of differences in TBR between Grade 2 and Grade 3 astrocytomas IDH1 mut supports the view that they are considered as a single subgroup of lower grade gliomas. CONCLUSION: PET/CT with 11C-methionine has limited potential to assess the IDH status of diffuse gliomas. High TBR is associated with malignant glioma with wild-type IDH1 gene or oligodendroglial structure.